Most epidemiologic studies of risk factors for Alzheimer's disease are limited to clinically diagnosed disease. This epidemiologic study proposes to continue investigating the pathologic mechanisms linking risk factors to the clinical expression of Alzheimer's disease. In the initial funding period, we found that 1) the apolipoprotein E e4 allele increased risk of clinical disease through an association with Alzheimer's disease pathology; 2) education reduced the likelihood that Alzheimer's disease pathology was expressed clinically; 3) Alzheimer's disease pathology is more likely to be expressed as clinical disease in women than in men; and 4) cerebral infarcts made a separate contribution to dementia but did not increase the likelihood that Alzheimer's disease pathology is expressed clinically. We also found that risk factors for Alzheimer's disease and common age-related pathologic indices can affect some cognitive abilities while sparing others, suggesting that studies limited to global measures of cognition may miss potentially important associations. The present application proposes to investigate the pathologic mechanisms linking HMG CoA reductase inhibitors (statins) and diabetes to clinical disease and to investigate additional hypotheses aimed at understanding sex differences in the clinical expression of Alzheimer's disease pathology. The proposed study will continue to take advantage of the risk factor information, longitudinal quantitative clinical data collected proximate to death, and brain tissue available through the Religious Orders Study, which performs annual clinical evaluations on more than 900 older nuns, priests and brothers who have agreed to brain donation after death. Hypothesis testing requires collecting new post-mortem data and linking it to available risk factor information and clinical data in innovative analyses. The findings from the proposed study could have important implications for therapeutic intervention and the prevention of Alzheimer's disease. [unreadable] [unreadable]